Ischemia has been widely studied in the retina, because of its proposed role in glaucoma, anterior ischemic optic neuropathy (AION), retinal and choroidal vessel occlusions, diabetic retinopathy, retinopathy of prematurity (ROP) and traumatic optic neuropathy. Thus studying the basic mechanisms underlying retinal ischemia is of substantial clinical interest. In retinal ischemia, energy depletion leads to necrotic cell death in the most severely affected areas, whereas apoptotic neurons are concentrated in the area of the ischemic territory, where the insult is milder. Necrosis of tissue leads to inflammatory and toxic activation of professional phagocytes, whereas the elimination of apoptotic cells by phagocytes stimulates the synthesis of anti- inflammatory and protective factors. Hence, the combination of different types of dead cells in tissue can determine the predominance of either toxicity or protection derived from phagocytes. The predominance of necrotic over apoptotic cells in ischemic tissue can mediate additional inflammatory stress in ischemic tissue. Our preliminary data and the literature suggest that such inflammatory stress can be responsible for a significantly greater amount of neuronal damage after retinal ischemia. We hypothesize that cell death related inflammatory stress makes a statistically significant contribution to the pathology of retinal ischemia. This hypothesis will be tested in a series of experiments outlined in the following specific aims: 1) To determine whether the predominance of necrotic over apoptotic signals influences the increased severity of post-ischemic damage in the retina;2) To determine whether the predisposition of cells to necrosis governs the increased severity of post ischemic damage in the retina;3) To determine the role of phagocyte interactions with dead cells on the increased severity of post-ischemic damage in the retina. Validation of our hypotheses will generate a potentially new list of targets for novel drugs which are aimed at reducing damage following retinal ischemia. PUBLIC HEALTH RELEVANCE: Retinal ischemia is a common cause of visual impairment and blindness. Predisposition to cell death via necrosis or apoptosis as a result of retinal ischemia could mediate inflammatory stress and consequently affect lesion size and the potential for recovery. The studies outlined in the specific aims will provide a better understanding of the effects of necrotic and apoptotic signals in the pathology of retinal ischemia and can stimulate the discovery of innovative strategies to help prevent the loss of vision in patients with ischemic injury.